Nutritional status, alongside physical exercise, is a crucial component in determining functional health in old age. The benefits of caloric restriction (without malnutrition) in prolonging life and postponing functional decline in mammals are well-established. Though many physiological changes occur on reduction of caloric intake, it is unclear which of these are responsible for the salutary effect on aging of this regimen. The goal of this research is to identify the mechanisms underlying the life-extending and anti-aging effects of caloric restriction. The yeast Saccharomyces cerevisiae will be used for this purpose. This choice will allow immediate focus on the cellular and molecular mechanisms involved, by eliminating consideration of systemic functions. The rationale behind the choice of model system is the well-known fact that caloric restriction results in a reduction in circulating glucose and insulin and the novel finding that reduction in caloric content of the growth medium by altering glucose concentration markedly extends yeast life span and metabolic potential. The initial signals, signaling pathways, and downstream effectors of this caloric restriction response on yeast life span will be examined. The hypothesis is that caloric restriction exerts its effects by changing the way in which glucose is metabolized and that the changes in cell physiology involve specific signaling pathways. The research will involve an examination of different nutritional protocols coupled to the genetic manipulation of metabolic and signal transduction pathways. If will include a careful biochemical analysis of the metabolic consequences and an evaluation of global changes in gene activity. The results of the proposed research have important implications for aging, diabetes, and cancer.